Ten Things to Know About Ten Imaging Studies: a Preventive Cardiology Perspective ( “ASPC Top Ten Imaging ”)

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American Journal of Preventive Cardiology 6 (2021) 100176

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American Journal of Preventive Cardiology

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State-of-the-Art Review

Ten things to know about ten imaging studies: A preventive cardiology perspective ( “ASPC top ten imaging ”)

Harold E. Bays a,∗, Amit Khera b, Michael J. Blaha c, Matthew J Budoﬀ d, Peter P. Toth e,f a Louisville Metabolic and Atherosclerosis Research Center, 3288 Illinois Avenue, Louisville KY 40213 USA b UT Southwestern Medical Center, Dallas, TX USA c Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore MD USA d Department of Medicine, Lundquist Institute at Harbor-UCLA, Torrance CA USA e CGH Medical Cener, Sterling, IL 61081 USA f Cicarrone center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD USA

a r t i c l e i n f o a b s t r a c t

Keywords: Knowing the patient’s current cardiovascular disease (CVD) status, as well as the patient’s current and future CVD Coronary artery calcium imaging (CAC) risk, helps the clinician make more informed patient-centered management recommendations towards the goal

Coronary computed tomography angiography of preventing future CVD events. Imaging tests that can assist the clinician with the diagnosis and prognosis of

(CCTA) CVD include imaging studies of the heart and vascular system, as well as imaging studies of other body organs ap- Cardiac ultrasound plicable to CVD risk. The American Society for Preventive Cardiology (ASPC) has published “Ten Things to Know Echocardiography

Nuclear myocardial perfusion imaging (MPI) About Ten Cardiovascular Disease Risk Factors.” Similarly, this “ASPC Top Ten Imaging” summarizes ten things

Cardiac magnetic resonance (CMR) to know about ten imaging studies related to assessing CVD and CVD risk, listed in tabular form. The ten imaging Cardiac catheterization studies herein include: (1) coronary artery calcium imaging (CAC), (2) coronary computed tomography angiog- Intravascular ultrasound (IVUS) raphy (CCTA), (3) cardiac ultrasound (echocardiography), (4) nuclear myocardial perfusion imaging (MPI), (5) Coronary optical coherence tomography (OCT) cardiac magnetic resonance (CMR), (6) cardiac catheterization [with or without intravascular ultrasound (IVUS) or coronary optical coherence tomography (OCT)], (7) dual x-ray absorptiometry (DXA) body composition, (8) hepatic imaging [ultrasound of liver, vibration-controlled transient elastography (VCTE), CT, MRI proton density fat fraction (PDFF), magnetic resonance spectroscopy (MRS)], (9) peripheral artery / endothelial function imaging (e.g., carotid ultrasound, peripheral doppler imaging, ultrasound ﬂow-mediated dilation, other tests of endothelial function and peripheral vascular imaging) and (10) images of other body organs applicable to preventive cardiology (brain, kidney, ovary). Many cardiologists perform cardiovascular-related imaging. Many non-cardiologists perform applicable non-cardiovascular imaging. Cardiologists and non-cardiologists alike may beneﬁt from a working knowledge of imaging studies applicable to the diagnosis and prognosis of CVD and CVD risk – both important in preventive cardiology.

What is already known about this subject? What are the new ﬁndings in this manuscript?

• The American Society for Preventive Cardiology (ASPC) has pub- • The “ASPC Top Ten Imaging ” summarizes ten things to know about lished “Ten Things to Know About Ten Cardiovascular Disease (CVD) ten important CVD-related imaging studies (listed in a tabular for- Risk Factors, ”[ 1 , 2 ] which summarizes major CVD risk factors, ac- mat). companied by sentinel reviews or guidelines relative to ten impor- • Non-cardiologists (e.g., primary care physicians, nurse practition- tant CVD risk factors. ers, physician assistants, gynecologists, endocrinologists, obesity • Assessing existing CVD and CVD risk through imaging is commonly medicine specialists, lipidologists, diabetologists etc.) may benefit used to stratify CVD risk and influence CVD prevention management. from an overview of CVD-related imaging studies commonly per- Diagnostic and prognostic imaging studies of the heart and other formed by cardiologists. Cardiologists may benefit from an overview body organs help clinicians with management decisions to prevent of imaging studies beyond the heart, but applicable to global pre- future CVD events. ventive cardiology –which are imaging studies often performed by non-cardiologists.

∗ Corresponding author. E-mail addresses: [email protected] (H.E. Bays), [email protected] (A. Khera), [email protected] (M.J. Blaha), mbudoﬀ@lundquist.org (M.J. Budoﬀ), [email protected] (P.P. Toth). https://doi.org/10.1016/j.ajpc.2021.100176 Received 1 December 2020; Received in revised form 16 March 2021; Accepted 19 March 2021 2666-6677/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

• In addition to the “Top Ten ” things to know about CVD imaging stud- 3. Appropriate use [ 4 , 5 ] ies, citations are listed in the applicable tables to provide the reader more in-depth resources (e.g., illustrative guidelines and other ref- • The choice of cardiac imaging studies should be based upon estab- erences) pertaining to each imaging category. lished “Appropriate Use ” criteria, [ 4 , 5 ] and individual patient presentation. • Appropriate imaging studies are those where the clinical benefits and value in an individual patient exceed the risk ( Reference Chart 1 ) 1. Introduction and cost, through providing clinically meaningful information about CVD and CVD risk, beyond clinical judgment alone. The intent of the “American Society for Preventive Cardiology • Appropriate use of imaging studies includes procedures most likely (ASPC) Top Ten Imaging ”is to help primary care clinicians and car- to provide safe and definitive answers to the diagnostic questions diology specialists keep up with the ever-increasing pace of diagnos- raised, and least likely to prompt further imaging studies and in- tic and prognostic imaging studies applicable to preventive cardiol- vasive downstream procedures, irrespective of the initial imaging ogy. Imaging studies focused on the heart are often performed by study results. In other words, in the interest of limiting the risks and cardiologists and/or radiologists and help with diagnosis and progno- costs of multiple imaging procedures, the choice of cardiac imaging sis. Other imaging studies may also help in CVD risk stratification, procedure should focus on which procedure is likely to provide the and include imaging studies of the peripheral vasculature, body fat, greatest amount of actionable information applicable to the individ- liver, brain, kidney, and ovary. The “ASPC Top Ten Imaging ” sum- ual patient, in the safest manner possible. marizes ten things to know about ten CVD-related imaging studies, • Clinicians should be cautious and judicious in cardiac imaging stud- listed in tabular formats. These ten imaging studies include: (1) coro- ies in patients at low CVD risk, especially for imaging studies that nary artery calcium (CAC) imaging and scoring, (2) coronary computed have low specificity in patients at low CVD risk. Low specificity car- tomography angiography (CCTA), (3) cardiac ultrasound (echocardio- diac imaging in low CVD risk patients may often lead to false positive graphy), (4) nuclear myocardial perfusion imaging (MPI), (5) cardiac results. False positive findings on cardiac imaging may needlessly magnetic resonance (CMR), (6) cardiac catheterization [with or with- prompt more invasive, more costly, and potentially unnecessary ad- out intravascular ultrasound (IVUS) or coronary optical coherence to- ditional testing and/or procedures, resulting in more health risk than mography (OCT)], (7) dual x-ray absorptiometry (DXA) body composi- benefit. tion, (8) hepatic imaging [ultrasound of liver, vibration-controlled tran- • Selecting the most appropriate imaging test should take into con- sient elastography (VCTE), CT, MRI proton density fat fraction (PDFF), sideration whether the patient is symptomatic or asymptomatic. magnetic resonance spectroscopy (MRS)], (9) peripheral artery / en- Performing cardiac imaging studies with low selectivity in asymp- dothelial function imaging (e.g., carotid ultrasound, peripheral doppler tomatic patients at low CVD risk has a higher risk of false positive imaging, ultrasound flow-mediated dilation, other tests of endothelial findings than cardiac imaging studies with high selectivity in symp- function and peripheral vascular imaging) and (10) images of other tomatic patients at high CVD risk ( Reference Chart 2 ). body organs applicable to preventive cardiology (brain, kidney, ovary). • Procedures having the most robust evidence to support use in screen- ( Fig. 1 ) ing for coronary artery disease in asymptomatic individuals include The intent is not to create a comprehensive discussion of all imaging family history assessment for premature CVD, CVD risk factor as- studies applicable to CVD assessment. Nor is this document intended to sessment, and CVD and CHD risk scores. [ 1 , 24 ] Additional diagnos- be a comprehensive discussion of each imaging study. Rather, the intent tic procedures having evidenced-based support in screening asymp- is to focus on common imaging studies having implications for preven- tomatic individuals include CAC scoring, with some suggestion that tive cardiology. For a more in-depth discussion of these CVD imaging carotid artery ultrasound can assist with CVD risk stratification. studies, this “ASPC Top Ten Imaging ”provides updated guidelines and [24] Little evidence supports the routine clinical use of cardiac rest- other selected references in the applicable tables. ing or stress imaging testing in asymptomatic patients. Possible exceptions (albeit with lower level evidence as noted per guidelines) include coronary CTA among selected, asymptomatic individuals at high CVD risk, or stress electrocardiogram in physically inactive pa- 2. Purpose of cardiac imaging tients at higher CVD risk who plan to start a rigorous physical exercise program. [24] • Cardiac imaging helps assess the degree of CVD, which is important • The selection of the most appropriate imaging test should be based in stratifying current CVD risk and determining management strate- upon the patient presentation. A common clinical scenario that di- gies toward preventing future CVD events. CVD risk factor manage- rectly impacts management directed at CVD prevention is the eval- ment is often more aggressive and often prioritized to patients most uation of chest pain, which typically involves various disease endo- likely to benefit, which often includes those with diagnosed CVD or types: (1) angina due to obstructive coronary artery disease (CAD) otherwise at increased CVD risk. with fractional flow reserve ≤ 0.80; (2) microvascular angina with • Cardiac imaging may help further stratify patients at intermediate coronary flow reserve < 2.0 and/or index of microvascular resistance CVD risk, as otherwise determined by coronary heart disease (CHD) > 25); (3) microvascular angina due to small vessel spasm (which risk scores [ 1 , 3 ]. can be assessed by intracoronary acetylcholine administration); (4) • Cardiac imaging results may help decide who to treat, what to treat, vasospastic angina due to epicardial coronary spasm (which can and when to treat, as well as how aggressively to treat atheroscle- be assessed by intracoronary acetylcholine administration); and (5) rotic lesions (e.g., revascularization) and/or CVD risk factors (e.g., noncoronary etiology (i.e., patients found to have normal coronary dyslipidemia, hypertension, hyperglycemia) –all for the purpose of anatomy and normal function via cardiac imaging). [6] helping prevent future CVD events. • While “ischemia and no obstructive coronary artery ” (INOCA) dis- • Extracardiac images of other body organs such as body composition ease can be assessed by the invasive coronary reactivity tests de- (android and visceral fat) liver (hepatic fat), brain (cerebral vascular scribed above, common noninvasive cardiac imaging studies ap- disease), kidney (vascular abnormalities), ovary (polycystic ovarian plicable to coronary microvascular disease include PET, CMR, and syndrome) and peripheral vasculature (endothelial dysfunction) can echocardiography, with invasive imaging studies including coro- also provide insight regarding other CVD risk factors and need for nary flow reserve via coronary angiography. [7] Similarly, causes potential treatment of these CVD risk factors. of “myocardial infarction with nonobstructive coronary arteries ” H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Fig. 1. Cardiac and other organ imaging relevant to preventive cardiology.

(MINOCA) include cardiac microvascular disease (i.e., microvascu- ○ Cardiomyocyte injury and ﬁbrosis can be evaluated by CMR and lar plaque, thrombosis), coronary vasospasm, and coronary artery CTA. [ 18 , 19 ] dissection. [8] Imaging studies to assess MINOCA include coronary ○ Microvascular dysfunction can be evaluated by PET and CMR. angiography with or without intravascular ultrasound or optical co- [12] herence tomography, as well as possibly intracoronary acetylcholine ○ Hybrid imaging includes: if coronary spasm is suspected. [ 9 , 8 , 10 ] Yet other cardiac imaging ■ PET/CT and PET/MRI: Assesses perfusion, cardiac viability, studies to help assess MINOCA include echocardiography, [10] with and atherosclerosis [ 20 , 21 ] PET and CMR useful to assess coronary microvascular dysfunction. ■ CT- Fractional Flow Reserve (FFR): Provides anatomic (i.e. [ 11 , 12 ] luminal and plaque) and physiologic/functional imaging data • Most instances of coronary artery disease involve macrovascular dis- to assess obstructive CAD [ 22 , 23 ] ease leading to obstruction and often clinically manifest by angina ■ Cardiac catheterization and FFR: Provides (invasive) and myocardial infarction. Even among patients with coronary anatomic and functional assessment of CAD [24] microvascular disease, most such patients also have macrovessel • CAC added to SPECT or PET may help further identify coronary atherosclerosis. [7] However, a sole focus on coronary macrovascu- artery plaque and better stratify risk [ 25 , 26 ] lar disease may underdiagnose cardiac disease in patients with coro- • CCTA added to CAC scoring may help improve the assessment of nary microvascular disease as often occurs in women. [7] Therefore, total plaque burden and better discriminate risk of death and/or selecting the most appropriate imaging study is best determined by myocardial infarction among symptomatic patients with suspected the patient presentation, and the information reasonably derived by coronary artery disease. [ 27 , 28 ] the imaging study performed on an individual patient. • Although it may have low speciﬁcity, CAC scoring is illustrative of ○ Coronary anatomy can be assessed by CAC, CCTA, CMR and car- a cardiac imaging study of high sensitivity, limited invasiveness, diac catheterization. [13] and low radiation exposure ( Reference Charts 1 & 2 ). CAC is often ○ Cardiac diastolic dysfunction can be evaluated by echocardio- performed in asymptomatic patients to help stratify CVD risk (see gram and CMR. [ 14 , 15 ] Section 1 and Table 1 below). [ 10 , 7 ] ○ Myocardial perfusion can be assessed by SPECT, PET, and CMR. [ 16 , 17 ] H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Reference Chart 1 Invasiveness and patient radiation exposure regarding various imaging procedures. Radiation exposure for some procedures may be less than listed via use of ultra-low dose radiation protocols involving stress-only imaging. Some common diagnostic procedures are listed at the bottom of the table for reference/illustrative purposes. [ 37 , 38 ].

Procedure Invasiveness Patient radiation exposure ∗

Contemporary coronary artery calcium CT Noninvasive, no contrast ~1 mSv [ 39 , 40 , 41 ] (CAC)

Contemporary coronary CT angiography Requires injection of contrast material (i.e., iodine) 1.0 - 5 mSv ∗∗ [ 42 , 43 , 44 , 45 ] (CCTA) Cardiac ultrasound / echocardiogram Noninvasive. If unable to physically exercise, then 0.00 mSv (no radiation) dobutamine may be injected to mimic exercise. May include contrast (i.e., agitated saline or commercial ultrasound contrast agents). [46] Nuclear myocardial perfusion imaging (MPI) • SPECT perfusion imaging Intravenous administration of nuclear contrast with 10 -15 mSv with technetium-99 [48] imaging at rest, followed by walking on a treadmill 25 –30 mSv with thallium-201 [48] (seldom with another injection afterwards of nuclear contrast. used in current clinical practice) If unable to physically exercise, then an A2A adenosine receptor agonists (i.e., regadenoson coronary vasodilator for cardiolite stress test) can be injected to mimic exercise

• PET perfusion imaging Requires injection of radiotracer (e.g., 50 mCi of 4 mSv with 82rubidium or 13ammonia [49]

82rubidium or 20 mCi of 13ammonia for rest and (older reports suggest higher radiation stress perfusion). [47] If unable to physically exercise, exposure) [ 48 , 47 ] then pharmacologic stress testing can be achieved via the vasodilators regadenoson, adenosine, dipyridamole, or inotropic/chronotropic agents such as dobutamine with or without atropine • MUGA ventricular imaging (seldom Requires injection of radiotracer 5 –10 mSv with use in current clinical practice) technetium-99m-pertechnetate [50] CMR Most cardiac protocols involve injection of contrast 0.00 mSv (no radiation) (i.e., gadolinium) Cardiac catheterization Cardiac catheterization involves insertion of a 2 –7 mSv for diagnostic cardiac catheter tube into the artery or vein in the groin, catheterization [51] neck, or arm, which is then threaded into the heart. 10 mSv or higher for interventional catheterization [ 52 , 52 ] DXA total body composition scan Noninvasive ≤ 0.001mSv for typical body composition (minimal radiation; technicians not required to wear garments to protect from radiation) Hepatic imaging • Ultrasound of liver Noninvasive 0.00 mSv (no radiation) • VCTE/ﬁbroscan Noninvasive 0.00 mSv (no radiation) • CT May involve injection of contrast (e.g., iohexol) 3.0 mSv • MRI-PDFF May involve injection of contrast (i.e., gadolinium) 0.00 mSv (no radiation) • MRS May involve injection of contrast (i.e., gadolinium) 0.00 mSv (no radiation) Carotid ultrasound, peripheral doppler Noninvasive 0.00 mSv (no radiation) imaging, ultrasound ﬂow-mediated dilation, and pulse amplitude tonometry Fingertip infrared light transmission photoplethysmograpy for endothelial function

Daily background radiation 0.007 mSv Yearly background radiation 3.0 mSv Roundtrip Transatlantic Flight 0.100 mSv Chest X-ray 0.02 –0.1 mSv Mammogram 0.40 mSv DXA AP spine scan 0.001 – 0.004 mSv Older body PET / CT scans 15 - 25.0 mSv Older whole body CT scans 10 - 20 mSv

∗ The standard measure of radiation is Sievert (Sv) or millisievert (mSv) or microsievert (uSv) units where 1 Sv = 1000 mSv = 1,000,000 uSv. Humans have natural daily radiation exposure of about 0.007 mSv from soil, rocks, radon, and outer space.

∗∗ Quality CCTA images with ~1 mSv radiation exposure can sometimes be obtained in younger patients without overweight/obesity, or when utilizing low-dose CCTA protocols. [ 42 , 43 , 53 ] CMR = Cardiac magnetic resonance, CT = computerized tomography, DXA = Dual x-ray absorptiometry, FFR = Fractional ﬂow reserve, IVUS = Intravascular ultrasound, MRI = Magnetic resonance imaging, MRI-PDFF = MRI proton density fat fraction, MRS = Magnetic resonance spectroscopy, MUGA = Multiple- gated acquisition scan, OCT = Optical coherence tomography, PET = Positron emission tomography, SPECT = Single-photon emission computerized tomography, VCTE = Vibration-controlled transient elastography.

4. Cardiac exercise stress testing mend therapeutic interventions towards the goal of preventing future CVD events. Non-invasive cardiac imaging studies in patients with sta- Preventive cardiology incorporates both primary and secondary CVD ble coronary obstructive symptoms (stable ischemic heart disease or prevention. Understanding the extent of CVD disease in both asymp- “chronic coronary syndrome ”) can help diagnose ischemic heart disease tomatic and symptomatic patients helps the clinician better recom- and are often performed prior to cardiac catherization. [29] In most H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Reference Chart 2 Sensitivity and Speciﬁcity of Cardiac Imaging Studies [ 29 , 54 , 55 ].

Imaging Test Sensitivity Speciﬁcity

Anatomically signiﬁcant coronary artery disease ∗ Coronary Calcium Imaging/Score 98% 40% Exercise electrocardiogram 58% 62% Stress echocardiogram (Echo) 85% 82% Coronary computed tomography angiography (CCTA) 96% 82% Single-photon emission computed tomography (SPECT) 87% 70% Positron emission tomography (PET) 90% 85% Stress cardiac magnetic resonance (CMR) 90% 80%

Functionally signiﬁcant coronary artery disease ∗∗ Coronary computed tomography angiography (CCTA) 93% 53% CCTA with fractional ﬂow reserve (FFR) 85% 78% Single-photon emission computed tomography (SPECT) 73% 83% Positron emission tomography (PET) 89% 85% Stress cardiac magnetic resonance (CMR) 89% 87%

∗ Anatomically significant CAD is sometimes defined as > 50% stenosis of the left main coronary artery, 70% stenosis of any major coronary vessel, or 30 – 70% stenosis with fractional flow reserve of ≤ 0.8. [56]

∗∗ Heart function imaging involves assessing blood flow within coronary arteries. The significance of a coronary artery obstruction can be assessed by measuring (directly or virtually) the pressure differential before and after a coronary artery stenosis (fractional flow reserve). The cut-off point for functionally significant CAD is often reported as ≤ 0.8, with other flow coronary blood flow metrics being dependent on the individual imaging technique. [ 56 , 57 , 42 ]. cases, the use of imaging studies to diagnose ischemia is performed omimetic). Regadenoson is the most common pharmacologic vasodila- with exercise testing, such as through use of a treadmill or bicycle. tor used for pharmacological SPECT stress testing. [ 33 , 34 ] Imaging with exercise testing can enhance accuracy of the stress testing, especially in patients with non-interpretable electrocardiograms. 5. Imaging studies The purpose of physical exercise coupled with imaging studies is to evoke coronary (macro and micro) blood flow, and promote other func- Safety considerations of imaging studies include the degree of their tional cardiovascular responses, during times of greater oxygen and nu- invasiveness and amount of radiation exposure ( Reference Chart 1 ). trient demands of the heart (i.e., during times of “stress ”such as via [35] Invasiveness is defined here as access to the body via inserting exercise). a diagnostic device or injecting imaging media through incision or per- Thus, stable patients suspected of myocardial ischemia who are able cutaneous puncture. Potential radiation exposure may be especially im- to exercise, and who have interpretable ECG/s, are best “stressed ”via portant in cardio-oncology. [36] physical exercise (i.e., treadmill or bicycle). Incorporating exercise in The most invasive CVD imaging study is cardiac catheterization. a cardiac “stress test ” allows for non-imaging assessment of hemody- ( Reference Chart 1 ) Cardiac catheterization remains the initial imaging namic response (i.e., heart rate, blood pressure), ST- segment analysis, procedure of choice for patients whose history, signs, symptoms and/or and onset of dysrhythmias. Stress electrocardiography alone is reported CVD imaging test results suggest high risk for myocardial dysfunction to have sensitivity and specificity of 50 – 80%, depending on the source (e.g., high CVD risk features on a cardiac exercise stress test). This is and patient population studied. [ 30 , 29 ] ( Reference Chart 2 ) In patients especially true if it is anticipated the cardiac catheterization may be with ECG abnormalities (e.g., left bundle branch block, changes consis- accompanied by a therapeutic intervention (i.e., PCI, thrombectomy, tent with left ventricular hypertrophy, ST-T wave changes), the addition atherectomy). Complications of cardiac catheterization include bruis- of heart imaging (e.g., echocardiography or MPI such as SPECT or PET) ing/bleeding at the catheter insertion site, myocardial infarction, stroke to exercise cardiac stress testing may help identify and quantify cardiac and other thrombotic complications, vascular injury, cardiac dysrhyth- dysfunction and/or ischemia. mias, infection, contrast induced nephropathy, or allergic reaction to A patient at low to intermediate CVD risk with a negative car- the contrast dye (i.e., iodine). diac stress test [i.e., demonstrating no chest pain and no electrocardio- The invasiveness, radiation exposure, and cost associated with car- graphic evidence of ischemia after undergoing standard exercise pro- diac catheterization have prompted development of alternative nonin- tocols and achieving ten metabolic equivalents (METS)] is at low risk vasive imaging procedures, many having limited radiation exposure. Ra- for future CVD events and or CVD mortality. [31] However, among pa- diation exposure is important because ionizing radiation contributes to tients with exercise treadmil stress tests suggesting possible ischemia, cell death, cellular injury, or cell mutation potentially leading to can- then depending on CVD risk, only 39% may subsequently have posi- cer. (Non-ionizing radiation includes electric and magnetic fields, radio tive imaging/angiogram evidence of atherosclerosis. [32] Thus, among waves, microwaves, infrared, ultraviolet, and visible radiation, which patients presenting with intermediate likelihood of CVD, exercise car- have insufficient energy to ionize atoms or molecules.) The degree of diac stress testing (i.e., treadmill or bicycle) plus cardiac imaging (e.g., radiation exposure is dependent on the dose of tracer infused, length echocardiogram, MPI, or PET) is more specific than an exercise stress of the imaging procedure, and the number of times the procedure is test alone. Furthermore, in patients with uninterpretable ECG’s, or in performed. Examples of CVD imaging studies with limited invasiveness patients unable to exercise, and/or who undergo pharmacologic cardiac include CAC, CCTA, & MPI. CVD imaging studies with limited invasive- stress testing, concomitant heart imaging studies are often required. ness and no or minimal radiation exposure include CMR and ultrasound. Patients unable to undergo adequate exercise stress testing (e.g., rel- (See Reference Chart 1 ) ative immobility due to deconditioning, frailty, obesity, stroke, orthopedic impairments, neuropathy, lung disease) may require pharmacologic stress testing. Examples of pharmacologic stress agents include 5.1. Computerized tomography (CT) coronary artery calcium (CAC) [58] regadenoson (A2a receptor agonist), adenosine (nonselective adenosine receptor agonist), dipyridamole (nonselective vasodilator and an- A coronary artery calcium (CAC) score utilizes CT to assess the tiplatelet agent that raises adenosine levels), and dobutamine (sympath- amount of calcium found in coronary arteries. Arterial calcium reflects H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Table 1 Ten things to know about computerized tomography coronary artery calcium (CAC) measurements.

(1) For most patients, the higher the CAC score, the higher the atherosclerotic burden and the higher the risk of a subsequent CVD event. (2) The Multi-Ethnic Study of Atherosclerosis Risk Score ( https://www.mesa-nhlbi.org/MESACHDRisk/MesaRiskScore/RiskScore.aspx ) assesses CHD risk based upon sex, age, race/ethnicity (e.g., Caucasian, Chinese, African American, and Hispanic), diabetes, smoking, family history of myocardial infarction, total cholesterol, high density lipoprotein cholesterol, systolic blood pressure, lipid lowering medications, hypertension medications and CAC scoring . [ 3 , 61 , 41 ] The Astronaut Cardiovascular Health and Risk Modification (Astro-CHARM) Coronary Calcium Atherosclerotic Cardiovascular Risk Calculator ( http://astrocharm.org/ ) is an ASCVD risk calculator that incorporates multiple ASCVD risk factors, including age, sex, systolic blood pressure, hypertension treatment, total and high density lipoprotein cholesterol, smoking, diabetes mellitus, family history of myocardial infarction, high sensitivity C-reactive protein and CAC scores . [62] (3) Patients most likely to benefit from CAC testing include asymptomatic individuals not known to have CVD, but who are 40 years and older without diabetes mellitus, individuals in whom primary CVD prevention therapeutics are being considered (e.g., statins), and/or individuals having borderline to intermediate 10-year ASCVD risk estimate of 5 –20% (i.e., borderline risk = 5 –7.5% and intermediate risk = 7.5 –20%). [ 41 , 63 , 64 ] (4) CAC scoring is generally not recommended for patients at low, < 5% 10-year ASCVD risk or patients with known CVD or patients at high, greater than 20% 10-year ASCVD risk. (5) Generally, a CAC score of > 0 –400 AU identifies individuals at minimal to mild to moderate CVD risk. An individual with a CAC score of 1 –99 may have a risk of CVD death, myocardial infarction, or unstable angina of 2 % in ~2 years. An individual with a CAC score of 100 –400 may have a risk of CVD death, myocardial infarction, or unstable angina of 4% in ~2 years. [65] In appropriate individuals, statin therapy is strongly

indicated when the CAC score is > 100 AU, [63] or ≥ 75 th percentile. [64] (6) A CAC score of zero AU suggests a low risk of subsequent CVD event (i.e., acute myocardial infarction, coronary death, stroke, revascularization) over at least the next 8 years. [66] Individuals with an initial CAC score of zero may consider a second scan 3-7 or more years later. [67] Unless the patient has intervening onset or worsening of CVD risk factors or diminished adherence to healthful nutrition and physical activities, individuals with double-zero CAC may not need an additional scan in the near future afterwards, because their risk of a CVD is ≤ 2% within 8-years after the repeat CAC score. [66] (7) A CAC score of ≥ 1000 AU represent a unique very high-risk phenotype of extreme coronary atherosclerosis with mortality outcomes commensurate with high-risk secondary prevention patients. [68] Such patients are at very high risk for a CVD event. [66] Similarly, patients with

high baseline CAC scores of ≥ 400 AU are also at high CHD/ASCVD risk ∗ (10 – 15% ten-year ASCVD risk); repeat CAC scoring is not appropriate for patients with CAC scores ≥ 400 AU, especially if treated with statins. [69] Patients with baseline CAC scores of 100 – 399 AU may have a > 5% 10-year ASCVD risk and be candidates for statin therapy. If statin therapy is implemented, then repeat CAC scoring may provide little additional benefit. [69] Patients with CAC scores of 1 –100 AU who elect to defer statin therapy or other preventive measures may benefit from repeat CAC in 5 years. [69] Especially if statin therapy is implemented, once a CAC score is found to be ≥ 100, then it is unclear that repeat CAC scores provide additional, clinically meaningful information. (8) Individuals with a positive CAC score of potential unclear clinical significance include patients with extensive calcification due to older age, patients with kidney disease (vascular medial sclerosis), patients treated with statins (i.e., reports suggest statins may increase CAC in some patients), and some patients with high levels of physical activity. [ 58 , 70 , 71 , 72 ] Given that CAC scores are unlikely to regress, CAC scores do not track response to cardiovascular preventive therapy (i.e., response to statins). While alcohol drinkers in general may have increased frequency of atherosclerotic plaque in the coronary arteries despite reduced or zero CAC scores, [ 73 , 74 ] heavy consumption of hard liquor may sometimes increase CAC scores. [ 75 , 76 ] (9) Individuals with a negative CAC score of potential unclear clinical significance include younger individuals who may have non-calcified atherosclerosis, patients with microvascular dysfunction, such as some women (and men) with non-obstructive ischemic heart disease (as may be assessed by PET). [77] (10) A low CAC score should not negate CVD risk factor management. For example, a low CAC score in a patient otherwise at high CVD risk should not give a false sense of security, and interpreted as negating the need for aggressive lipid management (e.g., stopping statin therapy in patients with Familial Hypercholesterolemia, who while young, may still have “soft ” uncalcified plaque).

Sentinel Guidelines and References 2021 National Lipid Association Scientiﬁc Statement on Coronary Artery Calcium Scoring [60] 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol [64] 2018 Coronary Calcium Score and Cardiovascular Risk [41] 2020 Coronary Calcium StatPearls [58] 2018 Coronary Artery Calcium: If Measuring Once Is Good, Is Twice Better? [69]

∗CHD = coronary heart disease (e.g., myocardial infarction or death from coronary heart disease)

∗ASCVD = Atherosclerotic cardiovascular disease is often defined as acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, peripheral artery disease, and aortic aneurysm –all of atherosclerotic origin [64] . vascular injury, inflammation, and repair. Coronary calcium is a marker contrast. [41] The Agatston score reflects the total area of calcium de- of plaque burden. It is not a measure of plaque vulnerability to rup- posits in coronary arteries, and the density of the calcium. ture or degree of coronary stenosis. Due to vessel remodeling early in CAC Agatston Unit (AU) scores and coronary plaque burden can be atherosclerosis, enlargement of coronary arteries may occur, mitigat- categorized as: [59] ing signs or symptoms of stenosis, despite substantial plaque burden. • 0: No identifiable calcified coronary atherosclerosis This pathogenic clinical scenario is often clarified by CAC. Other car- • 1–100: Calcification suggestive of mild coronary atherosclerosis diac imaging (i.e., with exercise stress testing) are more appropriate for • 100 to 400: Calcification suggestive of moderate coronary patients with angina and/or obstructive CAD. However, CAC is a non- atherosclerosis invasive cardiac procedure that can assess plaque burden, that is best • 400 or above: Calcification suggestive of severe coronary atheroscle- used in asymptomatic patients to help guide the need for further cardiac rosis evaluation or help determine the timing and degree of aggressiveness in • 1000 or above: Calcification suggestive of extreme coronary managing existing CVD risk factors. [29] atherosclerosis CAC scores may be increased with older age, men versus women for same age, metabolic syndrome, high blood glucose, high blood pres- In a Scientific Statement from the National Lipid Association, CAC sure, increased atherogenic lipoprotein cholesterol burden, cigarette scoring: [60] smoking, chronic kidney disease, and elevated C-reactive protein lev- • Informs ASCVD risk discrimination and reclassification els. [58] Assessment of coronary artery calcium is most often performed • Aids in ASCVD risk prediction, regardless of race, gender, or ethnic- by multidetector computed tomography (MDCT); CAC does not require ity H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Table 2 Ten things to know about coronary computed tomography angiography (CCTA) [29] .

(1) CCTA has a high negative predictive value, such that if negative, then clinically meaningful CVD risk. CCTA may be especially valuable in assessing patients with chest pain or related symptoms, but without known CHD and who are at low to intermediate CVD risk. CCTA guided changes in management can improve clinical outcomes. [82] (2) CCTA is a potential non-invasive imaging test of choice in patients with symptoms of chest pain where obstructive CAD cannot be reasonably established by history and physical exam alone. (3) CCTA may also be helpful to rule out left main CAD. The absence of coronary artery stenosis with CCTA imaging is associated with a favorable prognosis. (4) Evaluation of the severity of coronary stenosis can be derived from estimating pressure differences via “virtual ” fractional ﬂow reserve derived

from CCTA (FFRCT ). [83] (5) CCTA can assess non-obstructive coronary artery plaque, which can inform CVD preventive management. Management decisions guided by CCTA in patients with stable chest pain may reduce CHD and MI mortality at 5 years, without prompting a higher rate of coronary angiography or coronary revascularization. [84] (6) Poor image quality and severe calcification can overestimate CCTA coronary artery stenosis. (7) CCTA is not recommended in patients with extensive coronary calcification (which may occur with older age and kidney failure), cardiac dysrhythmias (including tachycardia), significant obesity, and in patients unable to hold their breath –all which may adversely affect image quality. (8) CCTA image quality may be impaired in patients with prior cardiac revascularization. (9) The contrast with CCTA is contraindicated in patients with contrast dye allergies. (10) Contrast (i.e., iodine) induced acute kidney injury occurs due to contrast-mediated hypoperfusion, direct tubular toxicity, and vasoconstriction. CCTA contrast should be used with caution in patients with kidney insufficiency and warrants adequate fluid intake in those receiving contrast. [85] Additional risk factors for CCTA contrast induced nephropathy beyond renal insufficiency (i.e., estimated glomerular filtration rate < 45 ml

min / 1.73m 2 ) include severe heart disease, dehydration, diabetes mellitus, multiple iodinated doses in a short time interval ( < 24 h) and use of nephrotoxic medications, such as non-steroidal anti-inﬂammatory drugs and diuretics. [86]

Sentinel Guidelines and References 2021 Epicardial fat and coronary artery disease: Role of cardiac imaging [81] 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: Recommendations for cardiovascular imaging [29] 2018 Coronary CT Angiography and 5-Year Risk of Myocardial Infarction [84] 2015 Outcomes of anatomical versus functional testing for coronary artery disease [87] 2015 Cardiac CT vs. Stress Testing in Patients with Suspected Coronary Artery Disease: Review and Expert Recommendations [88]

• Aids the clinician to allocate statin therapy based on ASCVD risk atherosclerosis), left ventricular function (i.e. heart failure, cardiomy- • May inform decision-making about add-on therapies to statins, es- opathy) and structural heart disease (i.e., valvulopathy, congenital heart pecially if CAC scores are very high disease, aneurysm, cardiac tumor, pericarditis, endocarditis, aortic dis- • Aids decision-making about aspirin and anti-hypertensive therapy section, heart chamber thrombosis). [89] Approaches to echocardiography include transthoracic chest wall approach or transesophageal ap- Reference Chart 1 describes the relative radiation exposure with proach. Types of echocardiography include: [ 90 , 89 ] CAC. Table 1 lists ten things to know about computerized tomography coronary artery calcium (CAC) measurements. • M-mode: “Motion mode ” generates tracing images rather than pic- 5.2. Coronary computed tomography angiography (CCTA) ture images. • Doppler (previously known as B or “Brightness-mode ”): As- Atherosclerotic progression begins with early reversible subendothe- sesses blood flow and can be characterized as continuous-wave, lial lipid accumulation, early inflammation, and minimal fibrosis. Fur- pulsed-wave or color-flow. Continuous and pulse wave doppler ther atherosclerotic progression may lead to lipid plaque, chronic in- echocardiography images allow for calculated flow velocity, as well flammation, fibrosis, and perivascular adipose tissue remodeling – as estimates for volume and pressure gradients across heart valves. which if untreated, may ultimately become irreversible. [78] CCTA can • 2-D (two-dimensional) echocardiography: Provides cross- measure lipid rich plaque, [79] as well as perivascular fat and inflam- sectional real-time motion images of the heart mation. [ 80 , 81 ] • 3-D (three-dimensional) echocardiography: Able to view real-

Clinically, CCTA is a cardiac imaging study utilizing CT that is often time motion of the heart via 3-D images used to quantify coronary atherosclerotic burden. When combined with FFR, CCTA can help determine the functional significance of stenotic le- Stress echocardiography is reasonably sensitive and specific sions. With use of an iodine intravenous contrast agent, CCTA can visual- for diagnosing coronary artery disease in symptomatic patients. ize the coronary artery lumen. CCTA is sensitive for anatomically signif- ( Reference Chart 2 ). However, despite its noninvasive safety, “routine ” icant CAD (e.g., obstructive CAD and nonobstructive calcified plaques) echocardiograms should not be performed in asymptomatic patients and reasonably sensitive for functionally significant CAD. However, ( “inappropriate use ”), as this may lead to false positive or equivocal CCTA is not specific for functionally significant CHD. ( Reference Chart findings, resulting in unnecessary downstream consultations and proce- 2 ) [29] Reference Chart 1 describes the relative radiation exposure with dures. [91] Reference Chart 1 describes how cardiac ultrasound results CCTA. Table 2 lists ten things to know about coronary computed tomog- in no radiation exposure. Table 3 lists ten things to know about echocar- raphy angiography (CCTA). diography. 5.3. Cardiac ultrasound (echocardiography)

Echocardiography utilizes ultrasound waves (sound wave range be- 5.4. Nuclear myocardial perfusion imaging (MPI) [29] yond that audible by humans) to provide hemodynamic information about heart function. When accompanied by stress testing, echocardio- Nuclear myocardial perfusion imaging through Single Photon Emis- graphy is often used to assess myocardial ischemia (i.e., coronary artery sion Computed Tomography (SPECT) utilizes small amounts of nuclear H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Table 3 Ten things to know about cardiac ultrasound (echocardiography) [ 29 , 89 ]

(1) Transthoracic echocardiography is the most common approach, with transesophageal echocardiography preferred in patients with conditions that compromise transthoracic imaging quality (e.g., obesity, certain lung conditions). Contrast options include agitated saline or commercial ultrasound contrast agents ( Reference Chart #1 ). [46] Contrast echocardiography may improve diagnostic performance regarding left ventricular opacification or microvascular perfusion imaging. [92] (2) Transesophageal echocardiography may provide better resolution images of the left heart, evidence of potential endocarditis, mitral and aortic valves, and aorta (i.e., aortic dissection). (3) Doppler echocardiography can assess stroke volume, heart chamber pressure gradients, valvular regurgitations, and intracardiac shunts. (4) In patients with angina-like chest pain, echocardiography can help diagnose alternative cardiac etiologies of chest pain, identify regional wall-motion abnormalities, determine left ventricular ejection fraction, and evaluate diastolic dysfunction for stratification purposes (i.e., surgical risk based upon cardiac status). (5) As with stress SPECT, stress PET, and stress CMR, stress echocardiography provides cardiac functional assessment. (6) Echocardiography is commonly used to assess left ventricular ejection fraction, which is “normally ” ~50 - 70%. Heart failure with reduced ejection fraction (HFrEF) is defined as heart failure with ejection fraction < 50%. (7) While heart failure can occur with reduced ejection fraction, symptomatic heart failure can also occur with preserved ejection fraction (HFpEF) (i.e., ejection fraction ≥ 50%). [93] (8) Echocardiography may provide helpful information regarding microcirculatory dysfunction that may contribute to angina without obstructive lesions in major coronary arteries. Angina and ischemia-like electrocardiographic changes without wall motion abnormalities on echocardiography may suggest microvascular dysfunction. [ 94 , 95 ] (9) In many patients, echocardiogram assessment of heart function and anatomy can provide peri-operative risk stratification. (10) Echocardiogram assessment can provide cross-sectional and longitudinal cardiac assessment in patients undergoing chemotherapy, helping to monitor for potential adverse effects of chemotherapy on cardiac structure and function. Evidence of echocardiographic left ventricular global longitudinal strain may be reflective of subclinical ventricular dysfunction and provide prognostic information in patients receiving cardiotoxic chemotherapy. [96]

Sentinel Guidelines and References 2021 Novelties in 3D Transthoracic Echocardiography [97] 2021 Usefulness of Stress Echocardiography in the Management of Patients Treated with Anticancer Drugs [98] 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: Recommendations for cardiovascular imaging [29] 2020 Echocardiography update for primary care physicians: a review [89] 2004 Understanding the echocardiogram [90] tracer (i.e., the isotope technetium-99 or thallium-201) injected into ischemia with no evidence of obstructive CAD. [102] Along with heart the blood to assess myocardial segments that do not take up the tracer failure with preserved ejection fraction, other cardiac conditions that (i.e., damaged myocardium) or areas with delayed uptake of the tracer may occur more often in women include Takotsubo cardiomyopathy, (i.e., ischemic myocardium). SPECT can also help assess the patency cerebral small-vessel disease, preeclampsia, pulmonary arterial hyper- of grafted blood vessels after coronary bypass. Techetium-99 is a ra- tension, endothelial dysfunction in diabetes, diabetes cardiomyopathy, diotracer often attached to a small protein (sestamibi). Thallium-201 is rheumatoid arthritis, systemic lupus erythematosus and systemic sclero- typically supplied as thallous chloride. Technetium-99 has lower radi- sis, and small vessel cardiac disease –which suggests a common etiologic ation exposure and is preferred; Thallium-201 is rarely used in current linkage of these cardiac conditions. [103] An illustrative strategy that clinical practice. ( Reference Chart 1 ) The radiotracers are generally in- may help balance safety and diagnostic yield would be to employ ultra- jected into the blood with imaging occurring at rest, or with exercise low dose radiation protocols involving stress-only imaging, with SPECT (e.g., “nuclear stress test , ”“exercise thallium scan , ”“exercise technetium- or PET used when possible for patients undergoing MPI. [104] 99 sestamibe scan ”), or both. For patients unable to physically exercise, A multiple-gated acquisition (MUGA) scan involves utilizes a radio- then an A2A adenosine receptor agonist (i.e., regadenoson coronary va- tracer (e.g., technetium-99m-pertechnetate) attached to red blood cells sodilator for cardiolite stress test) can be injected as an alternative to to evaluate the size of the chamber of the heart. MUGA was historically exercise. among the most common cardiac imaging studies for measuring left ven- A positron emission tomography (PET) scan of the heart utilizes a tricular ejection fraction (LVEF) MUGA scans are currently seldom used radiotracer (i.e., often 82 rubidium or 13 ammonia for rest and stress per- in favor of other imaging studies such as echocardiography and CMR. fusion). [47] Uptake of the radiotracer by the myocardium is propor- Reference Charts 1 & 2 describe the radiation exposure using MPI tional to myocardial blood flow. Thus, coronary flow reserve can be techniques, as well as their sensitivity and selectivity. Table 4 lists ten added to PET to improve CVD risk assessment. Strengths of PET MPI things to know about nuclear myocardial perfusion imaging. include high diagnostic accuracy, safety with low radiation exposure (lower than SPECT), efficient with 5-min image acquisition times (may take only 30 minutes to perform), ability to accommodate ill or higher- 5.5. Cardiac magnetic resonance (CMR) risk patients, ability to assess patients with large body habitus, and ability to assess non-obstructive coronary microvascular dysfunction. CMR is an imaging study that utilizes magnetic, radio frequency [99] PET is often used as a noninvasive imaging test to assess coro- waves (not ionizing radiation) to create cross sectional/2-dimentional, nary flow reserve ( Table 5 ), that may assist with diagnosis, prognosis, 3-dimentional, and even 4-dimentional images. CMR can help assess and management of patients with a range of ASCVD, including both valvular heart disease, ischemic heart disease, cardiomyopathies, con- multivessel obstructive CAD and diffuse coronary microvascular dys- genital heart disease, cardiac tumors, and pericardial disease (pericardi- function. Cardiac microvascular dysfunction may be especially clinically tis). [ 115 , 116 , 117 ] CMR can also measure subendocardial and subepi- relevant in women, patients with heart failure with preserved ejection cardial perfusion to assess for potential coronary microvascular dysfunc- fraction, metabolic syndrome, diabetes mellitus, cardio-oncologic com- tion in patients with nonobstructive coronary artery disease. [118] De- plications, and inflammatory-related disease. [ 100 , 101 ] Patients with termination of the value of CMR for imaging of cardiac anatomy such stable ischemic heart disease (SIHD) vary in their cardiac anatomy and as MINOCA is evolving. [119] Among examples where stress CMR may function. In addition to obstructive coronary lesions, it is estimated that be cost effective include patients with stable ischemic heart disease and 3 –4 million men and women in the US have symptoms of myocardial non-diagnostic coronary CT angiography. [120] Utilization of CMR for H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Table 4 Ten things to know about nuclear myocardial perfusion imaging (MPI).

(1) SPECT is a perfusion imaging study that typically uses technetium-99 ( 99mTc). 99mTc produces less radiation than thallium-201 ( 201TI), ~6 mSV

versus ~17 mSV respectively. This helps explain why 201TI is often only used during shortages of 99mTc. (2) MPI may utilize different tracers, depending upon the imaging device, and purpose of the imaging (e.g., perfusion imaging, atherosclerosis imaging, metabolic imaging, inflammation imaging, and/or innervation/sympathetic imaging) [105] (3) The degree MPI accurately predicts CVD risk depends on “Appropriate Use. ” (see prior “Appropriate Use ” section). Appropriate use of MPI can help stratify CVD risk; inappropriate use of MPI may not help stratify CVD risk. [106] (4) MPI may help augment CAC CVD risk stratification. [26] (5) MPI imaging may help identify obstructive coronary artery disease as the etiology of chest pain. [107] (6) MPI can be used in patients with immobility, cardiac rhythm disorders, impaired kidney function, or presence of cardiac devices. (7) Over 50% of patients may be unable to adequately exercise during MPI, with an inability to achieve 85% of maximum predicted heart rate and 5 metabolic equivalents (METS). This often prompts the alternative of pharmacologic stress testing (regadenoson, adenosine, dipyridamole, dobutamine) [108] (8) If stress MPI is normal, resting MPI may be redundant and not necessary. [ 109 , 110 ] Employing stress MPI results alone may reduce radiation and cost. (9) PET has a high sensitivity and specificity to detect anatomic and functional atherosclerotic lesions useful for CVD risk stratification (Reference Chart 2). (10) As with CMR, PET may help identify functional abnormalities suggestive of microvascular CAD. [12]

Sentinel Guidelines and References 2021 Nuclear cardiology: state of the art [111] 2021 Nuclear Medicine SPECT Scan Cardiovascular Assessment, Protocols, and Assessment [112] 2020 Review of cardiovascular imaging in the Journal of Nuclear Cardiology 2019: Positron emission tomography, computed tomography, and magnetic resonance [113] 2020 Noninvasive Imaging of Ischemic Heart Disease and Coronary Microvascular Dysfunction in Women. [114] 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: Recommendations for cardiovascular imaging [29]

Table 5 Ten things to know about cardiac magnetic resonance (CMR).

(1) CMR may provide additional imaging information for patients when an echocardiogram is inconclusive, such as in patients with obesity. [121] (2) As with stress MPI via SPECT or PET, or stress echocardiography, stress CMR is an example of a non-invasive functional imaging test that can assess myocardial ischemia. [29] (3) As with PET, CMR may be useful as a noninvasive imaging study for patients with suspected coronary microvascular angina, which may be especially important for women. [122] (4) CMR assesses ventricular mass, volume, and systolic function, and can be used to assess valvular heart disease and cardiac remodeling. [123] (5) CMR can visualize cardiomyopathies, such as restrictive, hypertrophic, and dilated cardiomyopathies. [ 124 , 125 ] (6) CMR can assess pericardial disease (i.e., pericarditis). [126] (7) CMR can visualize congenital heart disorders and cardiac tumors. [126] (8) Some patients with claustrophobia may be unable/unwilling to undergo CMR; mild sedation may help (i.e., diazepam). [127] (9) Due to its magnetic field, CMR should not be performed on patients with devices or implants that are not certified as CMR safe (pacemakers, implantable cardioverter defibrillators, inner ear implants, neuromuscular stimulators, drug infusion pumps, intrauterine devices, metal fragments and uncertified brain aneurysm clips and dental implants). [128] CMR can be performed in patients with many orthopedic protheses (e.g., titanium), with some exceptions (e.g., certain screws). [129] (10) CMR contrast dye (i.e., gadolinium) should be use with caution in patients with severe kidney insufficiency, as this may increase the risk of nephrogenic systemic fibrosis. [130] CMR nephrogenic systemic fibrosis can occur months after exposure and may be manifest by erythematous and edematous skin plaques mainly to the extremities, joint contractures, and respiratory failure. Beyond renal dysfunction, other risk factors for gadolinium-based contrast nephrogenic systemic fibrosis include proinflammatory state (e.g., major surgery, infection, malignancy), thrombotic events, and high-dose erythropoietin dose. [131]

Sentinel Guidelines and References 2021 Cardiovascular Imaging in Obesity [121] 2020 Standardized cardiovascular magnetic resonance imaging (CMR) protocols: 2020 update [132] 2020 Society for Cardiovascular Magnetic Resonance (SCMR) Position Paper on clinical indications for cardiovascular magnetic resonance [133] 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: Recommendations for cardiovascular imaging [29] cardiac anatomic disease may be more limited in the US relative to other is then threaded into the heart. Contrast (e.g., iodine or gadolinium) countries. dye is injected into the heart and vessels to assess narrowing or block- Reference Chart 1 describes how CMR results in no radiation expo- ages of coronary arteries and assess cardiac structure (e.g., heart valves, sure. Stress CMR has a high sensitivity for detecting anatomically and left ventricular function). In addition to the imaging part of the proce- functionally significant CAD (e.g., obstructive CAD) ( Reference Chart 2 ), dure, catheterization may also allow for therapeutic PCI, repairing of but is less specific for anatomically significant CHD ( Reference Chart 2 ). septal defects, balloon valvuloplasty, or heart biopsy. Reference Chart In general, CMR is commonly used to evauate cardiomyopathy, and oc- 1 describes the invasiveness and relative radiation exposure of cardiac casionally as an alternative myocardial perfusion tool in the setting of a catheterization. stress test. Fractional flow reserve (FFR) is often obtained via cardiac catheter- Table 5 lists ten things to know about CMR. ization and represents the pressure differential before and after a coronary artery stenosis. As noted in Reference Chart 2 , the cut- < 5.6. Cardiac catheterization [with or without intravascular ultrasound off point for functionally significant CAD is often reported as 0.8. > (IVUS) or coronary optical coherence tomography (OCT)] [30] Thus, anatomically significant CAD is sometimes defined as 50% stenosis of the left main coronary artery, 70% stenosis of any major Cardiac catheterization is an invasive procedure that involves insert- coronary vessel, or 30–70% stenosis with fractional flow reserve of < ing a catheter into an artery or vein in the groin, neck, or arm, which 0.8. [30] H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Table 6 Ten things to know about cardiac catheterization.

(1) Cardiac catheterization, potentially followed by stent placement or revascularization, is a diagnostic procedure of choice in patients with acute coronary syndrome (e.g., myocardial infarction or unstable angina). (2) Several million cardiac catheterizations are performed per year, with the rate of major complications (e.g., death, myocardial infarction, stroke, unplanned coronary bypass grafting, and pericardial effusion) occurring < 1 per 1000 left heart catheterizations. (3) Iodine containing contrast material > 240 mg/kg utilized during cardiac catheterization within 7 days of cardiac surgery may increase the risk of acute kidney injury. [144] Acute renal failure represents 17% of complications of cardiac catheterization. Among the more common factors that may increase the risk for contrast induced nephropathy includes older age, presence of chronic diseases (e.g., hypertension and diabetes mellitus), high volume of contrast, heart failure, and previous kidney disease. Other associated factors for contrast induced nephropathy include hypotension, longer procedure time, and atrial fibrillation. [145] (4) In patients with intermediate lesions (30 –70%), FFR should be performed to assess for functional (hemodynamic) significance. (5) In stable patients with moderate or severe ischemia and without clinically significant angina or left main CAD (e.g., via CCTA), an initial invasive strategy of coronary catheterization with or without revascularization may not reduce the risk of ischemic CVD or death from any cause compared to medical therapy, suggesting that cardiac catheterization might reasonably be reserved for optimal medical therapy failure. [146] (6) IVUS characterizes (i.e., intramural and/or extramural) and quantifies (i.e., area, volume) atherosclerotic plaque. (7) Compared to cardiac angiography alone, IVUS provides incrementally additional information regarding the arterial vessel wall, vessel dimensions, and plaque characteristics that may help optimize stent placement and mitigate stent complications. [147] (8) IVUS can help evaluate stent failure (i.e., stent thrombosis or stent restenosis). (9) OCT is a catheter-based imaging technology that can characterize coronary artery plaque, identify vulnerable coronary artery plaque, characterize and identify intracoronary thrombosis (red and white thrombi), and assess neointima formation after stent placement. (10) OCT can provide guidance for coronary interventions, such as determine the lesion length and vessel lumen diameter, which may assist with PCI procedures.

Sentinel Guidelines and References 2020 Initial Invasive or Conservative Strategy for Stable Coronary Disease [146] 2020 Intravascular Ultrasound StatPearls. [134] 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: Recommendations for cardiovascular imaging [29] 2019 Safety and Risk of Major Complications with Diagnostic Cardiac Catheterization [148] 2018 Coronary Optical Coherence Tomography [135]

Intravascular ultrasound (IVUS) is an imaging technique that may may be independently and inversely related to CAC scores, [149] while be conducted during cardiac catheterization that utilizes sound waves cortical volumetric BMD may be independently and directly related to to assess both intramural (impinging on the coronary lumen) and extra- CAC scores. [150] While not often done clinically, emerging research mural (ectatic) atherosclerotic plaque. It is performed using a dedicated suggests that DXA can assess abdominal aortic calcification, which is a catheter with ultrasound-based technology to provide a cross sectional risk factor for ASCVD. [151] Increased abdominal aortic calcification is image with a 360° view of the vessel. [134] Coronary optical coher- associated with increased risk for osteoporosis [152] . ence tomography (OCT) is an intracoronary artery diagnostic imaging DXA is also a “gold standard ”to assess body composition. Many DXA study that can be performed during cardiac catheterization. Coronary scanners can assess percent body fat, android fat, visceral fat, lean body OCT can help visualize the microstructure of normal and diseased ar- mass, and bone mass. DXA scans also provide the clinician and patient teries and can identify calcified plaque and neointima formation after colorful images with detailed descriptions of personalized information stent placement. [135] regarding body composition. Reference Chart 1 describes the invasive- While OCT may provide better image resolution of the coronary ar- ness and relative radiation exposure of DXA. The risk of radiation expo- teries, IVUS has greater imaging penetration than OCT, where large sure is often about 5% of a standard chest X-ray, about the same as an lipid-rich plaques may impair the ability to image the vessel border with intercontinental flight; technicians do not have to wear radiation pro- OCT. [136] OCT requires contrast (often iodine-based), [137] which in- tective garments. creases the risk of contrast induced nephropathy. Alternative OCT con- Patients with increased android fat (i.e., abdominal and visceral adi- trasts such as dextran may help avoid acute kidney injury. [138] Con- posity) are at increased CVD risk. DXA assessment of body composition trast induced nephropathy [136] is a poor prognostic factor that of- can be obtained for a cross-sectional assessment at a point in time, and ten delays hospital discharge and increases costs. [139] In short, OCT for longitudinal assessment after implementation of healthful nutrition, may be superior to IVUS in assessing the cause of stent failure, cal- physical activity, anti-obesity pharmacotherapy, or bariatric surgery. cific coronary disease, and MINOCA. Conversely, [139] IVUS may be These longitudinal DXA assessments in patients at higher CVD risk are superior in patients with left main coronary artery disease, renal dys- not influenced by treatments such as statins. Table 7 lists ten things to function, aorto-coronary ostial lesions, and chronic total occlusion. know about dual x-ray absorptiometry (DXA) body composition. [139] Another example of an intra-coronary imaging study includes near infrared spectroscopy (NIRS). [140] Other functional intra-coronary 5.8. Hepatic imaging for NAFLD measures that can be obtained during cardiac catheterization intracoronary include instantaneous wave-free ratio (iFR), [141] index of As with obesity, nonalcoholic fatty liver disease (NAFLD) is a factor microvascular resistance (IMR), [142] and minimal luminal area (MLA). associated with increased CVD risk. [158] (1) NAFLD encompasses the

[143] spectrum of fatty liver not related to alcohol consumption (e.g., fatty

Table 6 lists ten things to know about cardiac catheterization [with liver and hepatosteatitis). While NAFLD can be cause by genetics, infec- or without intravascular ultrasound (IVUS) or coronary optical coher- tious diseases, and various medications, NAFLD is most often associated ence tomography (OCT)]. with, or caused by CVD risk factors such as obesity/adiposopathy, type 2 diabetes mellitus, dyslipidemia, and sleep disorders. While insulin resistance may be a contributing mechanism to each of these CVD risk 5.7. Dual x-ray absorptiometry (DXA) body composition factors, it is not the only mechanism. In one example, while obstructive sleep apnea (OSA) is often associated with insulin resistance, OSA can DXA is commonly used to assess bone mineral density (BMD) in pa- also contribute to NAFLD due to hypoxia, inﬂammation, endotoxemia, tients at risk for osteoporosis. In women, trabecular volumetric BMD and gut barrier dysfunction. [159] H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Table 7 Ten things to know about dual x-ray absorptiometry (DXA) body composition.

(1) DXA scans for body composition can measure percent body fat, android fat, visceral fat, lean body mass, and bone mineral density. (2) Lean body mass is defined as total body mass less nonessential or storage adipose tissue (i.e., water, protein, bone, essential body fat) and has wide variance among individuals, depending on an individual’s mass of muscle, organs, and bone, which in turn is largely dependent on height, gender, genetics, nutrition, physical activity and overall health. (3) An increase in body mass (lean body mass or adipose tissue mass) increases resting energy expenditure. (4) The Obesity Medicine Association has established cutoff points for percent body fat (% BF) for women: pre-obesity = 30 – 34% BF and obesity ≥ 35 BF%; for men pre-obesity = 25 – 29% BF and obesity ≥ 30 BF%. The American Council on Exercise Classification has no categorization for pre-obesity or overweight, and defines obesity as ≥ 32% BF for women and ≥ 25% BF for men. (5) Android and visceral adiposity correlate with increased CVD risk. Epicardial fat has direct adiposopathic potential to adversely affect the heart. Epicardial and visceral adipose tissue share the same mesodermal embryonic origin, directly correlate with one another; both are associated with increased coronary artery calcification. Adipocyte hypertrophy and adipose tissue expansion may result in adiposopathic endocrinopathies and immunopathies (e.g., hormonal and pro-inflammatory responses from adipocyte hypertrophy and adipose tissue accumulation) [ 153 , 154 ] that can directly contribute to CVD (i.e., epicardial proinflammatory signaling) and indirectly contribute to CVD (i.e., promotion of insulin resistance, high blood sugar, high blood pressure, and high blood lipids –all CVD risk factors). (6) Percent body fat by DXA measures may not always correlate well with other percent body fat assessment devices –sometimes having % BF values 10% higher or more. (7) For most DXA measures, the android region is defined as the area between the ribs and the pelvis; visceral fat is the intraabdominal fat surrounding body organs.

(8) While generally accurate for populations, body mass index (kilogram weight per meter squared height or kg/m 2 ) may not be accurate in assessing body fat in individuals, especially those with increased muscle mass or sarcopenia. While percent body fat more accurately reﬂects body composition, the greatest support in correlating body fat to CVD is central adiposity (measures of waist circumference), as well as android and visceral fat. According to the Obesity Medicine Association, “optimal ” android fat is < 3 pounds (~1400 grams) and optimal visceral fat is < 1 pound (~500 grams). Within individuals (particularly women) total percent body fat may not reﬂect android or visceral fat measures. Some women with increased overall percent body fat may have no detectable visceral fat via DXA; the average rate of onset of CVD in women is ~10 years later than men. [ 1 , 2 ] (9) Not all DXA facilities perform body composition (i.e., many DXA scans are performed exclusively for bone mineral density). Not all DXA can distinguish between visceral and subcutaneous fat, nor accomodate patients with higher body mass index (i.e., ≥ 350 pounds). (10) The addition of a waist circumference to other non-DXA measures of percent body fat (e.g., air displacement plethysmography, bioelectrical impedance, underwater weighing densitometry) may provide complementary prognostic information regarding CVD risk.

Sentinel Guidelines and References 2021 Obesity Medicine Association Obesity Algorithm [101] 2017 Visceral fat reference values derived from healthy European men and women. [155] 2015 Does Visceral Fat Estimated by DXA Independently Predict Cardiometabolic Risk in Adults? [156] 2014 Imaging Body Fat: Techniques and Cardiometabolic Implications [157]

Nonalcoholic fatty liver is commonly defined as ≥ 5% liver fat (hep- arteries, or perhaps regression with lipid-altering therapy. Such imaging atosteatosis) without hepatocellular injury. Nonalcoholic steatohepati- results could be reported after lipid efficacy publications and before CVD tis (NASH) is the presence of ≥ 5% hepatosteotosis, lobular inflamma- outcome result publications. Largely because of the lack of acceptance tion, plus hepatocellular injury (hepatocyte ballooning with or with- of CIMT studies by regulatory agencies in the drug development process, out fibrosis). Hepatosteatosis alone rarely progresses to cirrhosis and minimal improvement in predicting CVD risk beyond established CVD liver failure. Conversely, patients with NASH are at increased risk of risk scores, and because of misinterpretation and/or mischaracterization cirrhosis and liver failure. Diagnosis of NAFLD may include use or mea- of CIMT results, [168] CIMT studies are less commonly performed now surement of aspartate transaminase / alanine transaminase (AST/ALT) in CVD prevention pharmacotherapy development programs (i.e., lipid- ratio index, various serum biomarkers, NAFLD Fibrosis score, Fibrosis altering drugs). [169] However, international guidelines do support the 4 calculator, enhanced liver fibrosis score, fibrometer, fibrotest, and presence of plaque on CIMT as identifying patients at higher CVD risk. hepatascore. Hepatic imaging may include liver ultrasound, vibration- [158] controlled transient elastography (VCTE or Fibroscan), CT of the liver, The correlation of peripheral vascular disease with CAD is a justi- MRI proton density fat fraction, and magnetic resonance spectroscopy. fication why an ankle brachial index (ABI) of < 0.9 is considered an Table 8 lists ten things to know about hepatic imaging for NAFLD. atherosclerotic CHD risk-enhancing factor. [64] ABI is measured via doppler-aided blood pressure differential assessments, but typically does

5.9. Carotid ultrasound, peripheral Doppler imaging, ultrasound not involve imaging. Plethysmography is the measured changes in vol-

ﬂow-mediated dilation, other tests of endothelial function, and peripheral ume of an organ or body, as in air displacement plethysmography (BOD vascular imaging POD). [101] Plethysmography to assess venous ﬂow (e.g., evaluation of possible deep vein thrombosis) can be performed via impedance, ul-

Carotid plaques are atherosclerotic lesions located in the carotid ar- trasonography or air plethsmography. [170] Peripheral doppler imag- teries that increase the risk of stroke. Imaging studies to evaluate carotid ing (e.g., B-mode doppler ultrasound and duplex ultrasound) can assess artery atherosclerotic lesions include CT and MRI. [166] Another imag- both peripheral venous and arterial disease. [170] Emerging doppler ing technique includes carotid ultrasound, which utilizes sound waves techniques include pulse wave velocity, vascular optical tomographic to evaluate the anatomy of carotid arteries. Carotid ultrasound is a pro- (i.e., cross-sectional) imaging, and polymer-based sensors (i.e., hemo- cedure that also usually includes doppler assessment of carotid blood dynamic monitor or HeMo). [170]

flow. [167] Decades ago, it was commonplace in lipid-altering drug de- Endothelial dysfunction may be consequence and predictor of velopment that B-mode ultrasound carotid intima medial-media thick- atherosclerosis. An ultrasound flow-mediated dilation imaging study of ness (CIMT) imaging studies would be conducted in the interim between the brachial artery is a noninvasive tool utilized to assess endothelial shorter-term lipid efficacy clinical trials (e.g., often 12 week trials) and function and can be used to predict future CVD events. [171] While

CVD outcomes studies (e.g., 2–5 years). The rationale was to demon- ﬂow mediated dilation may improve on risk scores (i.e., Framingham strate potential lack of atherosclerosis disease progression in the carotid risk score) in predicting CHD, when adjusted for confounders, the as- H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Table 8 Ten things to know about hepatic imaging for NAFLD.

(1) Non-specific hepatic ultrasound may miss NAFLD with liver fat content < 20%. (2) Vibration-controlled transient elastography (VCTE or Fibroscan) is a non-invasive ultrasound technique that can measure controlled attenuation parameter (CAP), which is a measure of hepatic steatosis. VCTE can also measure hepatic “stiffness, ” which reflects congestion, inflammation, and hepatic fibrosis. (3) Hepatic computed tomography (CT) has limited use in clinical practice due to radiation exposure that exceeds other liver fat imaging studies. (4) Magnetic resonance imaging is commonly used to measure liver fat, via proton density fat fraction (MRI-PDFF) which can assess the entire liver and that can be used with multiple MRI platforms. (5) Magnetic resonance spectroscopy (MRS) can measure fat in small regions of interest; but not all MRI platforms have the capability to perform MRS. (6) Nutritional medical therapy directed towards reducing imaging presence of hepatic fat (NAFLD) are similar to a heart healthy diet, such as evidenced-based meal plans limiting saturated fats and limiting ultra -processed/refined carbohydrates (e.g., Mediterranean diet). [1] (7) Longitudinal hepatic imaging in patients with NAFD may help track progress of therapy, [160] such as after implementation of appropriate nutrition, as well as dynamic and resistance training that increases peripheral insulin sensitivity, reduce circulating free fatty acids and glucose, reduce lipotoxicity, increase hepatic fatty-acid oxidation, decrease fatty acid synthesis, and that may help prevent mitochondrial and hepatocellular damage. [161] (8) Among patients with overweight or obesity, weight loss of 3 –5% may reduce hepatic imaging consistent with steatosis, with weight loss of 7 – 10% usually needed to improve histopathological features of NASH (e.g., fibrosis). (9) No pharmacotherapy has an approved indication to treat NAFLD and reduce imaging findings of liver fat. However, vitamin E 800 IU may provide biochemical and histological improvement in fatty liver in some adult patients with NASH without diabetes mellitus. (10) Some drugs may reduce imaging findings of hepatic fat such as peroxisome proliferator activated receptor gamma agonists and glucagon like protein –1 receptor agonists.

Sentinel Guidelines and References 2018 Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis [162] 2018 The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. [163] 2017 Imaging evaluation of non-alcoholic fatty liver disease: focused on quantiﬁcation. [164] 2016 A comparison of liver fat content as determined by magnetic resonance imaging-proton density fat fraction and MRS versus liver histology in non-alcoholic fatty liver disease. Acta Radiol. [165] 2021 Obesity Medicine Association Obesity Algorithm [101]

Table 9 Ten things to know about carotid ultrasound, peripheral doppler imaging, ultrasound ﬂow-mediated dilation, other tests of endothelial function, and peripheral vascular imaging.

(1) Peripheral artery disease as assessed by ABI < 0.9. While not an imaging study, an ABI < 0.9 is considered an atherosclerotic CHD risk-enhancing factor. [64] (2) Peripheral artery disease can also be assessed by imaging studies such as peripheral doppler imaging. (3) Guidelines support the presence of plaque on CIMT as identifying patients at high CVD risk. [158] (4) Plethysmography is the measure of changes in volume, and is a technique most often used to assess venous ﬂow (i.e., evaluation of possible deep vein thrombosis). (5) Plethysmography for peripheral venous and arterial can be performed via impedance and ultrasound. (6) Imaging studies can assess endothelial dysfunction, which may be consequence and predictor of atherosclerosis. (7) An ultrasound ﬂow-mediated dilation imaging study of the brachial artery is a noninvasive tool utilized to assess endothelial function and can be used to predict future CVD events. (8) Duplex ultrasound, CTA, or MRA of the lower extremities is useful to diagnose anatomic location and severity of stenosis for patient with peripheral artery disease when revascularization is being considered. [179] (9) Invasive peripheral artery angiography is useful for patients with critical limb ischemia or patients with lifestyle limiting claudication having an inadequate response to guideline directed management and therapy in whom revascularization is being considered. [179] (10) Invasive and noninvasive angiography (e.g., CTA MRA) should not be performed for the anatomic assessment of patients with asymptomatic peripheral artery disease unless the delineation of anatomy would change treatment. [179]

Sentinel Guidelines and References 2019 Global perspective on carotid intima-media thickness and plaque: should the current measurement guidelines be revisited? [169] 2018 Peripheral vascular disease assessment in the lower limb: a review of current and emerging non-invasive diagnostic methods. [170] 2018 Endothelial Function: A Short Guide for the Interventional Cardiologist [178] 2017 Flow Mediated Dilation as a Biomarker in Vascular Surgery Research [180] 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. [179] sociation of brachial flow mediated dilation with CHD may no longer mon historic techniques to assess endothelial function include coronary be significant, and may not improve discrimination and classification of epicardial vasoreactivity via quantitative coronary angiography, coro- CVD risk within intermediate risk individuals. [172] nary microvascular function via Doppler, flow mediated dilation, venous Other imaging studies that can assess endothelial function include occlusive plethysmography and finger plethysmography. [177] While invasive atomic force microscopy, myographs, and before and after im- the non-research, clinical utility of endothelial function assessment re- ages of invasive intra-arterial administration of vasoactive substances. mains unclear, monitoring of endothelial function has the theoretical Non-invasive imaging studies of endothelial function include enclosed potential to provide information on vascular health, predictor of future zone flow mediated dilation, digital (finger) pulse amplitude tonometry, adverse cardiovascular events, and assessment of the effectiveness of digital photoplethsmography, arterial pulse wave analysis, and others. stent placement and medications such as statins, beta-blockers, and an- [ 173 , 174 , 175 , 176 ] From a cardiac standpoint, among the more com- giotensin converting enzyme inhibitors. [178] H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

Table 10 Ten things to know about imaging of other body organs applicable to preventive cardiology (brain, kidney, and ovary).

(1) In individuals without symptomatic cardiovascular, cerebrovascular, or peripheral vascular disease, CVD risk factors such as diabetes mellitus, obesity, hyperlipidemia, and cigarette smoking are independently associated with brain imaging changes before the manifestation of clinical cardiovascular or cerebrovascular disease. [181] (2) Brain imaging findings associated with CVD risk factors include: (a) structural brain changes such as reduction in whole-brain volume, (b) white matter changes such as white matter hyperintensities and microbleeds, and (c) functional brain changes such as reduced cerebral blood flow. [ 181 , 190 , 191 ] (3) Brain image findings of structural, white matter, and functional brain changes associated with CVD risk factors may contribute to cognitive decline. [ 190 , 192 ] (4) CVD risk factors that contribute to reduced whole brain volume on brain imaging include hypertension, obesity, dyslipidemia, and cigarette smoking. [ 181 , 193 ] (5) Even light physical activity can help maintain brain volume over time. [ 181 , 193 ] (6) Fibromuscular dysplasia is an arteriopathy that predominantly occurs in younger women that may result in aneurysm, dissection, or occlusion of the renal, carotid, vertebral arteries, and coronary arteries. Clinically, fibromuscular dysplasia may contribute to hypertension, neurological signs and symptoms, and dissection of an epicardial artery resulting in unstable angina, myocardial infarction, left ventricular dysfunction, or possibly sudden cardiac death. [194] Noninvasive imaging of the kidneys include duplex ultrasound, CT angiography, and magnetic resonance angiography. [195] Definitive diagnosis of fibromuscular dysplasia and imaging-directed potential treatment usually requires catheter-based angiography of the renal arteries, and possible percutaneous angioplasty. [196] Cardiac angiographic features of fibromuscular dysplasia include spontaneous coronary artery dissection, smooth narrowing of coronary arteries, intramural hematoma, coronary artery spasm, and tortuosity (historically described as “string of beads ”). [194] (7) Also, while not specifically applicable to kidney imaging, the presence of kidney disease can affect decisions regarding cardiac imaging: • The decision to perform cardiac imaging study in patients with CKD should be directed towards individuals at higher CVD risk (e.g., with symptomatic CVD) and those most likely to benefit from revascularization. [183] • Stress echocardiography, MPI SPECT, and MPI PET are safe in patients with kidney insufficiency. • Coronary CT angiography utilizes iodinated contrast which increases the risk of contrast-induced nephropathy; CMR utilizes gadolinium-based contrast agents that increase the risk of nephrogenic systemic fibrosis. [183] • Many patients with CKD have extensive coronary artery calcification, limiting the diagnostic value of CCTA. [183] (8) The findings of “cysts ” on imaging women with PCOS represent antral follicles arrested in development that accumulate follicular fluid giving the appearance of cysts. [197] Due to improved ultrasound imaging techniques, some believe the threshold for polycystic ovary morphology should be 19 –25 follicles per ovary, instead of the more established criteria of 12 or more follicles per ovary. [198] (9) The diagnosis of polycystic ovaries is usually made via ultrasound, which should not be performed for this purpose in girls < 8 years of age. [199] (10) The presence of polycystic ovary morphology is not required for the diagnosis of PCOS. The Rotterdam Consensus for PCOS includes two or more of the following: [200] • Hyperandrogenism (clinical or biochemical) • Ovulatory dysfunction (menstrual irregularities) • Polycystic ovary morphology by ultrasound

Sentinel Guidelines and References 2020 Cardiac imaging for Coronary Heart Disease Risk Stratiﬁcation in Chronic Kidney Disease [183] 2019 Chronic Kidney Disease and Coronary Heart Disease [185] 2018 Recent advances in renal imaging. [186] 2018 International evidence-based guideline for the assessment and management of polycystic ovary syndrome. [199] 2014 Brain imaging changes associated with risk factors for cardiovascular and cerebrovascular disease in asymptomatic patients [181]

Peripheral vascular imaging is often considered for patients with and cigarette smoking are independently associated with brain imag- suspected limb ischemia having noncompressible arteries (ABI > 1.4) ing changes before the clinical manifestation of cardiovascular or cere- or objectively measured obstruction (ABI ≤ 0.9). Even if ABI is within brovascular disease. Types of structural brain changes associated with the normal or borderline range, a nonhealing wound or gangrene of one or more of these CVD risk factors include reduction in whole-brain the extremities might suggest the need for additional diagnostic pro- volume, white matter changes, and functional brain changes such as re- cedures. Perfusion assessments include toe-brachial index, transcuta- duced cerebral blood flow. Identification of brain changes due to CVD neous oxygen pressure, and skin perfusion pressure. If the totality of risk factors represents an opportunity to intervene before irreversible this diagnostic evidence supports limb ischemia, then imaging stud- deleterious brain damage occurs. [181] ies to consider include duplex ultrasound, computed tomography an- Patients with chronic kidney disease (CKD) are at increased risk for giography (CTA), magnetic resonance angiography (MRA), or inva- CAD, with the risk for CVD increasing with worsening kidney function. sive angiography. [179] Table 9 lists ten things to know about carotid [1] Most cases of adult-onset CKD are due to the major CVD risk factors ultrasound, peripheral doppler imaging, ultrasound flow-mediated di- of diabetes mellitus and hypertension, with obesity, cigarette smoking, lation, other tests of endothelial function, and peripheral vascular and older age also risk factors for both CKD and CVD. [182] Patients imaging. with CKD are at increased risk for complications related to revascularization, and long-term results are less favorable compared to individu- 5.10. Imaging other body organs applicable to preventive cardiology als with normal kidney function. [183] Examples of the adverse CVD (brain, kidney, and ovary) consequences of CKD progression include non-atherosclerotic CVD, left ventricular hypertrophy, cardiac dysthymias, sudden cardiac death, dif- In addition to heart and peripheral vasculature, body composition, fuse arterial calcification, mitral annular and aortic valve calcification, and evaluation of hepatic fat, assessment of other organs may have [184] hemorrhagic stroke, and increased risk for mortality after a CVD applicability to preventive cardiology, such as the brain, kidney, and event. [185] Currently, kidney imaging techniques (e.g., ultrasound, ovaries. CT, and MRI) assess kidney size and density, nephrolithiasis, and crude Imaging of the brain can be achieved by multiple different tech- markers of parenchymal damage (e.g., gross anatomic defects such as niques, such as PET, MRI, MRS, and others. In persons without symp- systemic disease, malignancies, and obstructive nephropathy). Newer tomatic cardiovascular, cerebrovascular, or peripheral vascular disease, imaging methods may enhance non-invasive detection of structural, CVD risk factors such as diabetes mellitus, obesity, hyperlipidemia, functional, and molecular kidney changes, such as dynamic contrast- H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176 enhanced magnetic resonance imaging (DCE-MRI) and blood oxygen Michael J. Blaha reports grants from NIH, FDA, AHA, Aetna Foundation, level-dependent (BOLD) MRI, and the use of novel contrast agents, such Amgen and the following advisory boards: Amgen, Sanofi, Regeneron, as microbubbles and nanoparticles. [186] Regarding cardiac imaging in Novartis, Novo Nordisk, Bayer, Akcea, Kaleido, 89Bio, and consulting patients with CKD, the choice of cardiac imaging should be based on with Kowa, Inozyme. Matthew J Budoff has received research grants the clinical presentation, matching the desired information to the most from Novo Nordisk, Pfizer, Amgen, Amarin and Boehringer Ingleheim. appropriate imaging test, and the imaging procedure that avoids use of Dr Budoff has received honoraria from Amgen, Boehringer Ingleheim, potentially nephrotoxic agents. Lilly, Amarin and Astra Zeneca. Peter P. Toth has served as a consultant Polycystic ovary syndrome is among the most common endocrine for Amarin, Amgen, bio89, Kowa, Novartis, Resverlogix, Theravance; disorder in women of reproductive age and occurs due to an imbal- and speaker for Amarin, Amgen, Esperion, Merck, Novo-Nordisk. ance of reproductive hormones in pre-menopausal women (with some metabolic abnormalities potentially extending into perimenopause). References [187] The presence of polycystic ovaries alone may not be associated with increased CVD risk. [188] However, PCOS is often associ- [1] Bays HE, Taub PR, Epstein E, Michos ED, Ferraro RA, Bailey AL, et al. Ten things to know about ten cardiovascular disease risk factors. Am J Prevent Car- ated with CVD risk factors such as insulin resistance, glucose intoler- diol 2021;5:100149 . ance, diabetes mellitus, hypertension, dyslipidemia (increased triglyc- [2] Bays HE . Ten things to know about ten cardiovascular disease risk factors ( “ASPC erides and decreased high density lipoprotein cholesterol), metabolic Top Ten –2020 ”). Am J Prevent Cardiol 2020;1:100003 . [3] Blaha MJ , Whelton SP , Al Rifai M , Dardari Z , Shaw LJ , Al-Mallah MH , et al. Com- syndrome, increased C-reactive protein, increased CAC scores, increased paring risk scores in the prediction of coronary and cardiovascular deaths. JACC: carotid intima-medial thickness, endothelial dysfunction, and sleep ap- Cardiovas Imaging 2020:3302 . nea. [ 1 , 2 , 101 , 189 ] Table 10 lists ten things to know about imaging of [4] Wolk MJ , Bailey SR , Doherty JU , Douglas PS , Hendel RC , Kramer CM ,

et al. ACCF/AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2013 multi- other body organs applicable to preventive cardiology (brain, kidney, modality appropriate use criteria for the detection and risk assessment of stable and ovary). ischemic heart disease: a report of the American college of cardiology foundation appropriate use criteria task force, American heart association, american society

6. Conclusion of echocardiography, American society of nuclear cardiology, heart failure society of America, heart rhythm society, society for cardiovascular angiography and interventions, society of cardiovascular computed tomography, society for cardio- The “ASPC Top Ten Imaging 2021 ”is intended to be complementary vascular magnetic resonance, and society of thoracic surgeons. J Am Coll Cardiol to the “ASPC Top Ten CVD Risk Factors, ”and summarizes ten things to 2014;63:380–406. [5] Ladapo JA , Blecker S , O’Donnell M , Jumkhawala SA , Douglas PS . Appropriate use know about ten imaging studies related to CVD prevention. The “ASPC of cardiac stress testing with imaging: a systematic review and meta-analysis. PLoS Top Ten Imaging 2021 ” represents a starting point for those interested One 2016;11 e0161153-e . in CVD evaluation and CVD risk assessment. Knowledge of CVD cardiac [6] Sidik NP, McEntegart M, Roditi G, Ford TJ, McDermott M, Morrow A, et al. Ratio- nale and design of the British heart foundation (BHF) coronary microvascular func- and non-cardiac imaging can help guide preventive cardiology manage- tion and CT coronary angiogram (CorCTCA) study. Am Heart J 2020;221:48–59 . ment and treatment. Just as the practice of preventive cardiology is a [7] Taqueti VR , Di Carli MF . Coronary microvascular disease pathogenic mecha- whole-body discipline, so should clinicians engaged in preventive cardi- nisms and therapeutic options: JACC state-of-the-art review. J Am Coll Cardiol 2018;72:2625–41 . ology understand multi-organ imaging modalities that might assist in as- [8] Tamis-Holland JE , Jneid H , Reynolds HR , Agewall S , Brilakis ES , Brown TM , sessing CVD risk. Such imaging methods naturally include evaluation of et al. Contemporary diagnosis and management of patients with myocardial in- the heart. But imaging relative to cardiovascular disease prevention also farction in the absence of obstructive coronary artery disease: a scientiﬁc statement

from the American heart association.. Circulation. 2019;139:e891–908. includes dual x-ray absorptiometry (DXA) body composition, hepatic [9] Sucato V , Testa G , Puglisi S , Evola S , Galassi AR , Novo G . Myocardial infarction imaging, peripheral artery / endothelial function imaging, and images with non-obstructive coronary arteries (MINOCA): Intracoronary imaging-based of other body organs applicable to preventive cardiology (brain, kid- diagnosis and management. J Cardiol 2021 . ney, ovary). Many cardiologists engaged in preventive cardiology rou- [10] Scalone G, Niccoli G, Crea F. Editor’s choice- pathophysiology, diagnosis and management of MINOCA: an update. Eur Heart J Acute Cardiovasc Care 2019;8:54–62 . tinely perform heart-centered imaging. Many non-cardiologists engaged [11] Ferreira VM . CMR should be a mandatory test in the contemporary evaluation of in preventive cardiology routinely perform non-heart centered imaging "MINOCA". JACC Cardiovas Imaging 2019;12:1983–6 . applicable to preventive cardiology. Cardiologists and non-cardiologists [12] Vancheri F, Longo G, Vancheri S, Henein M. Coronary microvascular dysfunction. J Clin Med 2020;9 . alike may beneﬁt from a basic working knowledge of imaging studies [13] De Filippo M , Capasso R . Coronary computed tomography angiography (CCTA) applicable to preventive cardiology. and cardiac magnetic resonance (CMR) imaging in the assessment of patients presenting with chest pain suspected for acute coronary syndrome. Ann Transl Med 2016;4:255 .

Funding [14] Ramos JG , Fyrdahl A , Wieslander B , Thalén S , Reiter G , Reiter U , et al. Comprehen- sive cardiovascular magnetic resonance diastolic dysfunction grading shows very None. good agreement compared with echocardiography. JACC Cardiovas Imaging 2020 . [15] Konerman MC , Greenberg JC , Kolias TJ , Corbett JR , Shah RV , Murthy VL , et al. Re- duced myocardial ﬂow reserve is associated with diastolic dysfunction and de- Author contribution creased left atrial strain in patients with normal ejection fraction and epicardial perfusion. J Card Fail 2018;24:90–100 . [16] Klein R , Celiker-Guler E , Rotstein BH , deKemp RA . PET and SPECT tracers for my-

All authors reviewed, edited, and approved the submission and ap- ocardial perfusion imaging. Semin Nucl Med 2020;50:208–18 . proved responses to AJPC reviewer comments. Harold Bays MD served [17] Motwani M , Jogiya R , Kozerke S , Greenwood JP , Plein S . Advanced cardiovascular as medical writer, wrote the preliminary draft outline, incorporated au- magnetic resonance myocardial perfusion imaging: high-spatial resolution versus thor and reviewer edits, and submitted the manuscript. 3-dimensional whole-heart coverage. Circ Cardiovas Imaging 2013;6:339–48. [18] Ibanez B , Aletras AH , Arai AE , Arheden H , Bax J , Berry C , et al. Cardiac MRI end- points in myocardial infarction experimental and clinical trials: JACC Scientiﬁc Disclosures Expert Panel. J Am Coll Cardiol 2019;74:238–56 . [19] Ko SM , Hwang SH , Lee HJ . Role of cardiac computed tomography in the diagnosis of left ventricular myocardial diseases. J Cardiovasc Imaging 2019;27:73–92 . Harold Edward Bays’ research site has received research grants from [20] Rischpler C , Nekolla SG , Kunze KP , Schwaiger M . PET/MRI of the heart. Semin 89Bio, Acasti, Akcea, Allergan, Alon Medtech/Epitomee, Amarin, Am- Nucl Med 2015;45:234–47 . gen, AstraZeneca, Axsome, Boehringer Ingelheim, Civi, Eli Lilly, Espe- [21] Hoilund-Carlsen PF, Piri R, Gerke O, Edenbrandt L, Alavi A. Assessment of total– body atherosclerosis by PET/computed tomography. PET Clin 2020 . rion, Evidera, Gan and Lee, Home Access, Janssen, Johnson and John- [22] Asher A , Singhal A , Thornton G , Wragg A , Davies C . FFRCT derived from computed son, Lexicon, Matinas, Merck, Metavant, Novartis, NovoNordisk, Pﬁzer, tomography angiography: the experience in the UK. Expert Rev Cardiovasc Ther

Regeneron, Sanoﬁ, Selecta, TIMI, and Urovant. Dr. Harold Bays has 2018;16:919–29. [23] Conte E , Sonck J , Mushtaq S , Collet C , Mizukami T , Barbato E , et al. FFRCT and served as a consultant/advisor for 89Bio, Amarin, Esperion, Matinas, CT perfusion: A review on the evaluation of functional impact of coronary artery and Gelesis, and speaker for Esperion. Amit Khera has no disclosures. stenosis by cardiac CT. Int J Cardiol 2020;300:289–96 . H.E. Bays, A. Khera, M.J. Blaha et al. American Journal of Preventive Cardiology 6 (2021) 100176

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